Preclinical Toxicology Studies with Acyclovir: Genetic Toxicity Tests

Preclinical Toxicology Studies with Acyclovir: Genetic ToxicityTests. Clive, D., Turner, N.T., Hozier, J., Batson, A.G. andTucker, W.E., Jr. (1983). Fundam. Appl. Toxicol 3: 587–602.Acyclovir (ACV), an antiviral drug active in the treatment oforal and genital Herpes infections, has been evaluated for mutagenicand carcinogenic potential in a battery of in vitro and in vivoshort-termassays. Negative results were obtained in the following in vitrotests: Ames Salmonella, plate incorporation and preincubationmodification assays; E. coli polA⁺/polA^– DNA repair; yeast(S. cerevisiae D4) gene conversion; Chinese hamster ovary cells(HGPRT, APRT loci and ouabain-resistance marker); L5178 Y mouselymphoma cells (HGPRT locus and ouabain-resistance marker);and C3H/10Tmouse fibroblast neo-plastic transformation assay.All except the last assay were performed in the presence andabsence of an exogenous metabolic activation system. ACV waspositive at high concentrations x exposure times in the absenceof exogenous metabolic activation in the following in vitrosystems and at the indicated concentrations: BALB/c-3T3 neoplastictransformation (50 /µg/mL, 72 h exposure); human lymphocytecytogenetics (250–500 µg/mL, 48 h exposure); andL5178Y mouse lymphoma cells (TK locus, 400–2400 µg/mL,4 h exposure; predominantly small colony mutants of chromosomalorigin produced). No effects were seen in vivo (mouse dominantlethal assay; rat and Chinese hamster bone marrow cytogenetics)at up to maximum tolerated doses (MTD). An unusual clastogeniceffect was seen in Chinese hamsters at 5 times the MTD. Overall,positive effects were seen only at either high concentrations(250 µg/mL in vitro or plasma levels) or prolonged exposure(72 hr in the BALB/ c-3T3 neoplastic transformation assay).These studies support the view that ACV is a chromosomal mutagen,i.e., one which causes multi-locus damage but not single geneeffects. The significance of these results for the genetic riskof ACV to man is discussed.     

The Role of a Third and Possible Fourth Coronary Angioplasty for Recurrent Stenosis

From 1980 to 1985, 1,179 patients underwent percutaneous transluminal coronary angioplasty (PTCA) for the first time. Of these, 92 (7.8%) underwent a second PTCA, 25 (2.1%) a third, and 5 (0.4%) a fourth PTCA of the same vessel and site of the initial stenosis. Success rates for these groups were 78%, 87%, 88%, and 100%, respectively. The left anterior descending coronary artery (LAD) was involved in 14 (56%), the right coronary artery (RCA) in 9 (36%), and the circumflex coronary artery (CX) in 2 (8%). There were no deaths or emergency surgery due to the third and fourth PTCA. Follow-up after the last PTCA indicated symptomatic relief and an improvement in Canadian Cardiovascular Society functional class (CAHA) along with an increase in the exercise time on a standard Bruce stress test. We conclude that a third or fourth PTCA provides a safe and effective therapy for recurrent stenosis.     

Struggle for control: General practitioners in the Swedish health care system

This paper reports on findings on the perspectives of generalpractitioners (GPs) in Sweden since the introduction of theStockholm model. The research design was exploratory with theintention of discovering several perspectives shared by doctors.The subjects were asked to describe their work, how long theyhad been working and to describe whether they were familiarwith the Stockholm model. Questions also focused on professionalautonomy, the use of diagnostic related groups (DRGs), the Isolationof work and the possible impact on patient care. While previousresearch suggests that doctors may be losing autonomy, the experiencein Sweden, in particular, as it relates to GPs, may be different.Most of the doctors interviewed reported that the Stockholmmodel had increased productivity and efficiency, that economicincentives influenced their medical decisions and that medicaltreatment appears more patient focused than before. GPs reportedan enhanced social and economic status within the medical professionsince the introduction of the Stockholm model.     

The Effect of Phase Separation on Biphasic Waveform Defibrillation

It has been hypothesized that the defibrillafion efficacy of a biphasic shock is caused hy the large change in voltage between the two phases. This study examined the effects of separating the two phases in time thus splifting in half the rapid voltage change at phase reversal. The study was performed in three parts each using six dogs. Part I determined defibrillation thresholds (DFTs) for two exponentially truncated biphasic waveforms (3.5/2 msec and 6/6 msec) with interphase time delays of 0, 1, 2, 3, 4, 6, 8, and 10 msec. In Part II, probability of success curves were generated using an up down method with 15 shocks for each delay for the 3.5/2 msec biphasic waveform with inferphase delays of 0, 2, 3, 4, and 5 msec. In Part III, DFTs were determined using a 3.5/2 msec and 6/6 msec biphasic as well as a fhird waveform that consisted of two sequential 6-msec pulses of the same polarity with interphase delays of 0, 5, 10, 15, 20, 25. 50, and 100 msec. In all three parts the defibrillating cathode was a 6.17 cm² transvenous spring electrode positioned in the RV apex and the anode was a 113 cm² cutaneous left chest wall eiectrode patch. With all waveforms, the trailing edge voitage of the first phase was equal to the negative of the leading edge voltage of the second phase. There was no statistical difference in DFTs or in 50% successful defibriliation points for phase separations from 0 to 6 msec and 0 to 5 msec for Parts I and II, respectively. In Part I there was a significant increase in DFTs for phase separations of 8 and 10 msec compared to a phase separation of 0 msec. In Part III there was no significant difference for seporations of 0 and 5 msec; however, there was a significant increase in DFT requirements for separations from 5 to 50 msec, which then decreased with a separation of 100 msec for ail three waveforms tested. In conciusion, defibriilation efficacy was unchanged with phase separations up to 6 msec. With phase separation, the rapid voltage change during phase reversal is split in half and. thus, cannot explain the improved efficacy of biphasic waveforms.     

Acute Disseminated (Non-Lipid) Reticuloendotheliosis

In several publications W allgren has dealt with problems related to storage diseases. In 1940 he advanced the idea that the so-called acute reticulo-endotheliosis bears close relationship to Schüller-Hand-Christian's disease and that these two maladies represent only different types of one and the same underlying disturbance. Since then this idea has gained wider acceptance. The eosinophilic granuloma has also become incorporated in the same syndrome. In the following paper some of the inherent problems are discussed in a clinical conference at the Vanderbilt Pediatric Clinic.     

Cardiac Neoplasms: Current Diagnosis, Pathology, and Therapy

Cardiac neoplasms remain enigmatic because of their rarity and protean clinical manifestations. Although surgery for benign cardiac neoplasms seems straightforward, certain difficulties in diagnosis and extirpation often exist. Newer diagnostic modalities including intraoperative transesophageal echocardiography seem promising and may provide better planning for the surgeon. Moreover, cardiac transplantation has provided relief for some patients with irresectable benign neoplasms. As ventricular arrhythmias may emanate from benign tumors, electrophysiologically guided extirpation may provide helpful control. Malignant cardiac tumors remain the true challenge, whether primary or metastatic, as little surgical or medical progress has resulted. This review examines nearly all diagnostic, pathological, histologic, and therapeutic aspects of benign and malignant cardiac tumors. Moreover, the various surgical approaches necessary for removal of resectable neoplasms are detailed.